Adiponectin ameliorates hypoperfusive cognitive deficits by boosting a neuroprotective microglial response

Vascular cognitive impairment and dementia (VaD) is the second most common type of dementia caused by chronic vascular hypoperfusion. Adiponectin, one of the cytokines produced by adipocytes (adipocytokine), plays a role in CNS pathologies, but its specific function in VaD is unknown. Here, transcriptomic analyses on human brain tissues showed downregulation of adipocytokine/PPAR signaling in VaD patients, with prominent upregulation of pro-inflammatory responses. Using the murine asymmetric common carotid artery stenosis (ACAS) model, we discovered that the Adiponectin/PPARγ axis is essential in reducing chronic hypoperfusion-induced cognitive deficits via modulation of microglial function. Adiponectin levels in the plasma increased early after VaD induction, but decreased in the cerebrospinal fluid in the late phase of VaD. Adiponectin deficiency worsened hippocampus-dependent cognitive deficits, exacerbated neuroinflammation and microglia/macrophage activation, and amplified neuronal loss, but these behavioral and histological outcomes were rescued by adipoRon, a small molecule agonist of the Adiponectin receptors. AdipoRon boosted PPARγ expression and inhibited pro-inflammatory microglial responses in vitro, thereby protecting ischemic neurons in primary microglia-neuron cocultures. Microglia/macrophage-specific knockout of PPARγ abolished the neuroprotective effects of adipoRon. Collectively, these data confirm the importance of Adiponectin/PPARγ signaling in maintaining cognitive functions in chronic hypoperfusion-induced dementia, and thus provide novel therapeutic targets for VaD.